Download citation file:
From Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts.
Grant Support: In part by grants from the Howard Hughes Medical Institute (Dr. C.E. Seidman) and the National Institutes of Health (Drs. J.G. and C.E. Seidman).
Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1230.
Requests for Single Reprints: Christine E. Seidman, MD, Department of Genetics, Harvard Medical School, Room 256 NRB, 77 Louis Pasteur Avenue, Boston, MA 02115; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Wang: Department of Internal Medicine, Jackson Memorial Hospital, University of Miami, 1400 Northwest 12th Avenue, Miami, FL 33130.
Drs. J.G. Seidman and C.E. Seidman: Department of Genetics, Harvard Medical School, Room 256 NRB, 77 Louis Pasteur Avenue, Boston, MA 02115.
Author Contributions: Analysis and interpretation of the data: L. Wang, J.G. Seidman, C.E. Seidman.
Drafting of the article: L. Wang, J.G. Seidman, C.E. Seidman.
Critical revision of the article for important intellectual content: L. Wang, C.E. Seidman.
Final approval of the article: C.E. Seidman.
Statistical expertise: J.G. Seidman.
Obtaining of funding: C.E. Seidman, J.G. Seidman.
Administrative, technical, or logistic support: C.E. Seidman.
Collection and assembly of data: L. Wang, C.E. Seidman.
Unexplained cardiac hypertrophy, the diagnostic criterion for hypertrophic cardiomyopathy (HCM), occurs in 1 in 500 adults. Insights into the genetic cause and molecular pathophysiology of HCM are reshaping clinical paradigms for diagnosis and treatment of this common myocardial disorder. Human genetic studies have established that dominant mutations in the proteins that make up the contractile apparatus (the sarcomere) cause HCM. With the current availability of clinical gene-based diagnostics, pathogenic mutations in affected patients can be defined, which can suggest a clinical course and allow definitive preclinical identification of family members at risk for HCM. Genetic discoveries have also fos-tered mechanistic investigations in model organisms that are engineered to carry human HCM mutations. Novel therapeutic targets have emerged from these fundamental studies and are currently under clinical assessment in humans. The combination of contemporary gene-based diagnosis with new strategies to attenuate disease development and progression is changing the natural history of lifelong cardiac symptoms, arrhythmias, and heart failure from HCM.
The mass of the normal myocardium (A) is increased in HCM because of ventricular hypertrophy, which can be asymmetrical (B), concentric (C), or focal (not shown). Diastolic dysfunction in HCM leads to atrial enlargement and increases risk for atrial clots (C), an important cause of thromboembolic events in HCM. The normal myocyte histology (D) is perturbed in HCM, with marked enlargement and disarray of myocytes (E) (hematoxylin–eosin staining). Masson trichrome staining (F) reveals increased amounts of interstitial fibrosis (blue). HCM = hypertrophic cardiomyopathy.
Symbols denote sex (square, male; circle, female) and clinical status (solid, HCM; open, unaffected; slashed, deceased; green, status unknown). Analyses of the DNA of sarcomere genes (Table) identified a causal mutation in the β-myosin heavy-chain gene in the proband (arrow), which allowed gene-based diagnosis of all family members. The same mutation was found in adults with clinical evidence of HCM (+) but was absent in unaffected adults (−). Note that 5 children have preclinical HCM: They carry the β-myosin heavy-chain mutation but have no evidence of disease. HCM = hypertrophic cardiomyopathy.
Ca2+ enters the myocyte through the voltage-gated L-type Ca2+ channel and triggers CICR. Ca2+ is released from the SR through the RyR2 complexes comprising cardiac ryanodine receptor, calsequestrin, junctin, triadin, and sorcin. When one contractile protein in the sarcomere carries an HCM mutation (red stars), sarcomere contractility increases and relaxation diminishes. This results in abnormal Ca2+ cycling with slower Ca2+ reuptake of the SR by the SERCA pump and reduced Ca2+ content in the SR (blue arrows). Abnormal Ca2+ cytosolic concentration and mechanical dynamics of the mutant sarcomere stimulate signaling pathways in the nucleus that promote myocyte growth, premature myocyte death, and increased myocardial fibrosis. In model organisms that carry a human HCM mutation, early normalization of Ca2+ handling during the preclinical phase of disease attenuated the subsequent development of hypertrophy and fibrosis. CICR = Ca2+-induced Ca2+ release; HCM = hypertrophic cardiomyopathy; RyR2 = cardiac ryanodine receptor; SERCA = sarco/endoplasmic reticulum Ca2+–adenosine triphosphatase; SR = sarcoplasmic reticulum.
Please read the other comments before posting. Contributors must reveal any conflict
Comments are moderated and will appear on the site at the discretion of The American
College of Physicians editorial staff. Please be sure your email address is
updated in your account, otherwise the American College of Physicians will not be
able to contact you about your comment.
Anyone can submit a comment any time after publication, but only those submitted within 4 weeks of an article’s publication will be considered for print publication. One month after publication, editors review all posted comments and select some for publication in the Letters section of the print version of Annals. (Not peer reviewed)
Authors: No more than 5
Text: Word Limit 400 (excludes references), 5 references, no figures or tables
* = Required Field
Disclosure of Any Conflicts of Interest*
(applies to the past 5 years and foreseeable future) Indicate any potential conflicts
of interest of each author below, including specific financial interests and relationships
and affiliations relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria, speakers
bureau, stock ownership or options, expert testimony, royalties, donation of medical
equipment, or patents filed, received, or pending). If all authors have none, check
"No potential conflicts or relevant financial interests" in the box below. Please
also indicate any funding received in support of this work. The information will
be posted with your response.
The In the Clinic® slide sets are owned and copyrighted by the American College
of Physicians (ACP). All text, graphics, trademarks, and other intellectual property
incorporated into the slide sets remain the sole and exclusive property of the ACP.
The slide sets may be used only by the person who downloads or purchases them and
only for the purpose of presenting them during not-for-profit educational activities.
Users may incorporate the entire slide set or selected individual slides into their
own teaching presentations but may not alter the content of the slides in any way
or remove the ACP copyright notice. Users may make print copies for use as hand-outs
for the audience the user is personally addressing but may not otherwise reproduce
or distribute the slides by any means or media, including but not limited to sending
them as e-mail attachments, posting them on Internet or Intranet sites, publishing
them in meeting proceedings, or making them available for sale or distribution in
any unauthorized form, without the express written permission of the ACP. Unauthorized
use of the In the Clinic slide sets will constitute copyright infringement.
to gain full access to the content and tools.
Learn more about subscription options